WO2023282452A1

WO2023282452A1 - Virtual organoid generation method

Info

Publication number: WO2023282452A1
Application number: PCT/KR2022/006454
Authority: WO
Inventors: 양지훈; 송의정; 곽태환; 이시영
Original assignee: 주식회사 넥스트앤바이오
Priority date: 2021-07-09
Filing date: 2022-05-06
Publication date: 2023-01-12
Also published as: EP4369306A1; KR20230009707A

Abstract

The present specification provides: a method for generating a virtual organoid having various shapes and features; and a virtual organoid imaging method capable of obtaining the same effect as image data obtained from an actual organoid. The virtual organoid generation method according to the present specification may generate data relating to an organoid structure in a virtual space so as to apply the features of an actual organoid. The imaging method using the virtual organoid according to the present specification enables generation of image data which can obtain the same effect as capturing an image of an actual organoid.

Description

How to create virtual organoids

The present invention relates to virtual data generation, and more particularly, to a method for generating virtual organoid data.

The content described in this section merely provides background information on the embodiments described herein and does not necessarily constitute prior art.

Organoids, also called 'organoids' or 'similar organs', are organ-specific cell aggregates produced by aggregating and recombining cells isolated from stem cells or organ-derived cells through a three-dimensional culture method. Organoids include specific cells of an organ to be modeled, reproduce specific functions of an organ, and can be spatially organized in a form similar to that of an actual organ.

It has been reported that patient-derived tumor organoids can express the characteristics of cancer cells and tissues of patients as they are and reproduce the genetic mutation characteristics of cancer tissues of patients. Recently, high-throughput screening techniques have been developed that combine much more stable and physiological patient-derived organoids for use in early drug discovery programs and toxicity screens.

Organoids that can be used in cell therapy, biotissue engineering, new drug development, toxicology, and precision medicine require a large amount of analysis data on organoids to increase their utilization. In particular, in order to train an artificial intelligence model in the field of artificial intelligence, which is developing recently, a large amount of training data is required. However, there is a problem in that it takes a lot of time and money to fill all of the vast amount of learning data only with the data analyzed from the actual organoid.

[Prior art literature]

[Patent Literature]

(Patent Document 1) Patent Publication No. 10-2020-0081295, 2020.07.07

An object of the present specification is to provide a method for generating virtual organoids having various shapes and characteristics.

An object of the present specification is to provide a method for capturing virtual organoids capable of obtaining the same effects as image data obtained by capturing actual organoids.

This specification is not limited to the above-mentioned tasks, and other tasks not mentioned will be clearly understood by those skilled in the art from the description below.

The method for generating virtual organoids according to the present specification to solve the above problems is a method for generating organoids in a virtual 3-dimensional space, wherein a processor (a) generates random numbers, and units as many as the number according to the generated random numbers. generating an ellipsoid; (b) setting and arranging the center point of each unit ellipsoid generated in step (a) at arbitrary coordinates in a three-dimensional space; (c) generating as many cavity ellipsoids as the number of unit ellipsoids whose center points exist inside each unit ellipsoid; (d) generating lump data by removing the set of common ellipsoids from the set of unit ellipsoids; (e) converting the chunk data into voxel data according to a preset resolution; and (f) randomly arranging cells with respect to the voxel.

According to one embodiment of the present specification, the step (a) may be a step of generating a diameter length and a rotation angle with respect to three orthogonal axes with the center point of each unit ellipsoid as the origin using random numbers.

According to one embodiment of the present specification, step (b) may be a step of arranging the center point so that the boundary of each unit ellipsoid exists in a virtual 3D space.

According to one embodiment of the present specification, the step (c) may be a step of generating a diameter length and a rotation angle with respect to three mutually orthogonal axes with the center point of each hollow ellipsoid as an origin using random numbers.

According to an embodiment of the present specification, step (f) may include (f-1) setting a probability that a cell exists in each voxel; and (f-2) determining whether or not to place cells according to the set cell existence probability for each voxel.

According to an embodiment of the present specification, when two or more different cells exist, the step (f-1) may be a step of setting a probability such that only one of the two or more cells exists in each voxel.

The virtual organoid generation method according to the present specification may further include (g) assigning characteristic values to the arranged cells.

According to one embodiment of the present specification, the step (g) may be a step of assigning at least one characteristic value among the cell size, shape, and staining degree.

The virtual organoid generation method according to the present specification may be implemented in the form of a computer program written to perform each step of the virtual organoid generation method in a computer and recorded on a computer-readable recording medium.

An apparatus for generating organoids according to the present specification for solving the above problems is a device for generating organoids in a virtual three-dimensional space, generating random numbers, generating as many unit ellipsoids as the number according to the generated random numbers, Arrange the center point of each unit ellipsoid by setting arbitrary coordinates in the 3D space, create as many joint ellipsoids as the number of unit ellipsoids whose center point exists inside each unit ellipsoid, and create the joint ellipsoid in the set of unit ellipsoids and a processor generating chunk data by removing a set of v, converting the chunk data into voxel data according to a preset resolution, and randomly arranging cells with respect to the voxel.

The method for generating captured image data using a virtual organoid according to the present specification for solving the above problems is a method for generating captured image data using a virtual organoid generated in a virtual 3-dimensional space, wherein the processor (a) setting a position of a light source in a virtual 3D space; (b) setting a focal plane in a virtual 3-dimensional space; (c) calculating the brightness and sharpness of each cell in the virtual organoid in consideration of the position of the light source and the position of the focal plane; and (d) generating captured image data of the virtual organoid reflecting the brightness and sharpness of the calculated cells.

According to one embodiment of the present specification, step (a) may be a step of setting the light source to be located at the upper end of the virtual organoid in the Z-axis direction from the central region.

According to one embodiment of the present specification, step (b) may be a step of setting the focal plane to be located within the boundary surface of the virtual organoid.

Preferably, the step (b) may be a step of setting the normal of the focal plane to be parallel to the Z-axis of the virtual 3D space.

According to one embodiment of the present specification, in the step (c), the brightness of the cells is in inverse proportion to the square of the distance between the light source and each cell, and the sharpness of the cells is calculated in inverse proportion to the square of the distance between each cell and the focal plane. can be

In this case, the step (c) may be a step of calculating the brightness and sharpness of the cells in consideration of the degree of staining of the cells.

The method for generating captured image data using a virtual organoid according to the present specification is implemented in the form of a computer program written to perform each step of the method for generating captured image data using a virtual organoid in a computer and recorded on a computer-readable recording medium. It can be.

An apparatus for generating captured image data using a virtual organoid according to the present specification for solving the above problems is a device for generating captured image data using a virtual organoid generated in a virtual 3-dimensional space. Set the position of the light source, set the focal plane in the virtual 3D space, calculate the brightness and sharpness of each cell in the virtual organoid considering the position of the light source and the position of the focal plane, and calculate the cell It may include; a processor that generates photographic image data of virtual organoids in which the brightness and sharpness of are reflected.

Other specific details of the invention are included in the detailed description and drawings.

According to one aspect of the present specification, virtual organoids having various shapes and characteristics can be quickly and easily generated.

According to another aspect of the present specification, imaging data of a virtual organoid capable of obtaining the same effect as image data of a real organoid may be obtained.

According to another aspect of the present specification, a vast amount of captured image data using virtual organoids can be obtained, and the vast amount of captured image data can be used in various ways, such as artificial intelligence learning data.

The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

1 to 3 are flowcharts of a method for generating virtual organoids according to the present specification.

4 is a reference diagram for a unit ellipsoid.

5 is a reference diagram for lump data of virtual organoids.

6 is a reference diagram for voxelization.

7 is a reference diagram for random cell arrangement in voxels.

8 is a flowchart of a method for generating captured image data using virtual organoids according to the present specification.

9 is a reference diagram for calculating brightness and sharpness of cells.

10 is an example of a photographed image of a virtual organoid.

11 is another example of a captured image of a virtual organoid.

Advantages and features of the invention disclosed in this specification, and methods for achieving them, will become clear with reference to the embodiments described below in detail in conjunction with the accompanying drawings. However, the present specification is not limited to the embodiments disclosed below and may be implemented in a variety of different forms, and only the present embodiments make the disclosure of the present specification complete, and are common in the art to which the present specification belongs. It is provided to fully inform the technical person (hereinafter referred to as 'one skilled in the art') of the scope of the present specification, and the scope of rights of the present specification is only defined by the scope of the claims.

Terms used in this specification are for describing the embodiments and are not intended to limit the scope of the present specification. In this specification, singular forms also include plural forms unless specifically stated otherwise in a phrase. As used herein, "comprises" and/or "comprising" does not exclude the presence or addition of one or more other elements other than the recited elements.

Like reference numerals throughout the specification refer to like elements, and “and/or” includes each and every combination of one or more of the recited elements. Although "first", "second", etc. are used to describe various components, these components are not limited by these terms, of course. These terms are only used to distinguish one component from another. Accordingly, it goes without saying that the first element mentioned below may also be the second element within the technical spirit of the present invention.

Unless otherwise defined, all terms (including technical and scientific terms) used in this specification may be used with meanings commonly understood by those skilled in the art to which this specification belongs. In addition, terms defined in commonly used dictionaries are not interpreted ideally or excessively unless explicitly specifically defined.

In the process of extracting cells and culturing the extracted cells to produce organoids, which are organ-specific aggregates, it is necessary to examine whether the prepared organoids are spatially organized in a similar form to actual organs. To this end, a method of directly observing organoids is representative, but a method using artificial intelligence is considered to quickly examine a large amount of organoids.

Artificial intelligence for organoid inspection or discrimination requires a function to determine whether an organoid has a desired shape or what characteristics it has when an image of an organoid is input. In order to implement these functions, a large amount of image data for various organoids for organoid inspection or learning of discrimination models is required. However, it takes astronomical amounts of time and money to train an artificial intelligence model using image data taken from actual organoids. However, the present applicant came up with a virtual organoid to overcome these disadvantages. By creating various virtual organoids that reflect the characteristics of real organoids, and generating image data from virtual organoids as in the case of photographing real organoids, a large amount of image data for AI model learning can be created. . When an organoid inspection or discrimination model is trained using the image data generated in this way, time and cost can be significantly reduced compared to learning using actual organoid photographed images, and the performance of artificial intelligence can be significantly improved.

Hereinafter, the above-described virtual organoid generation method and captured image data generation method using the virtual organoid will be described with reference to the accompanying drawings.

The virtual organoid generation method according to the present specification can be largely divided into three steps: i) generation of unit spheroids and hollow spheroids, ii) generation of organoid clumps, and iii) cell arrangement. A virtual organoid according to the present specification is virtual data capable of mimicking a real organoid in a virtual three-dimensional space, and the method for generating a virtual organoid may be implemented in the form of a computer program that can be executed on a computer. Therefore, in describing the virtual organoid generation method according to the present specification, processing, calculation, output, and various logics of each step will be described as being executed by a processor known in the art to which the present invention belongs. The processor may include a microprocessor, CPU, application-specific integrated circuit (ASIC), other chipsets, logic circuits, registers, communication modems, data processing devices, and the like in the field of computer technology. In addition, when the virtual organoid generation method according to the present specification is implemented as software, the processor may be implemented as a set of program modules. At this time, the program module may be stored in the memory device and executed by the processor.

First, referring to FIG. 1 , in step S100, the processor may generate a random number N. The random number N corresponds to the number of unit ellipsoids to be generated later.

In the next step S110, the processor may set the variable k and input “k=0” as an initial value. The variable k is a variable for repeating the process of generating the unit ellipsoid N times.

In the next step S120, the processor may generate parameters of the unit ellipsoid. The parameters of the unit ellipsoid mean the length of the diameter from the central point and the degree of inclination (rotation angle) from the central axis. 4 is a reference diagram for a unit ellipsoid. 4, r1 (x-axis radius), r2 (y-axis radius), r3 (z-axis radius), a1 (x-axis rotation angle), a2 (y-axis rotation angle), a3 (z-axis reference) rotation angle). According to one embodiment of the present specification, in step S120, the processor determines the diameter lengths (r1, r2, r3) and rotation angles (a1, a2, a3) of three orthogonal axes with the center point of each unit ellipsoid as the origin. It can be generated through random numbers.

In the next step S130, the processor may arrange the center point of each unit ellipsoid by setting arbitrary coordinates (x _k , y _k , z _k ) in the 3D space. At this time, the processor may arrange the center point so that the boundary of each unit ellipsoid exists in a virtual 3D space. That is, a part of the tower body may exist outside the virtual 3D space so that a part of the ellipsoid is not lost.

In the next step S140, the processor may generate parameters of a cavity ellipsoid. In step S150, the processor may place the common ellipsoid inside the unit ellipsoid. Therefore, the number of cavity ellipsoids is equal to N, which is the number of unit ellipsoids, and each cavity ellipsoid can correspond 1:1 with each unit ellipsoid. In this specification, the cavity ellipsoid is data generated to form an internal hollow of a virtual organoid, and the hollow space will be described later. The parameters of the cavity ellipsoid are also the same as those of the unit ellipsoid, and the processor uses the center point of each cavity ellipsoid as the origin and the length of the diameters of the three orthogonal axes (r'1 (x-axis radius), r'2 (y-axis radius) ), r'3 (z-axis radius)) and rotation angles (a'1 (x-axis rotation angle), a'2 (y-axis rotation angle), a'3 (z-axis rotation angle)) as random numbers can be created through

On the other hand, the center point of the unit ellipsoid and the center point of the common ellipsoid need not necessarily coincide. That is, the center point of the unit ellipsoid may be different from the center point of the joint ellipsoid, and it is sufficient if the center point of the joint ellipsoid is located inside the unit ellipsoid. The processor may generate the separation degrees (dx _k , dy _k , dz _k ) from the center point (x _k , y _k , z _k ) of the unit ellipsoid by generating random numbers, and set the center point of the common ellipsoid according to the separation degree.

On the other hand, the entire cavity ellipsoid need not necessarily exist inside the unit ellipsoid. That is, the partial radius of the cavity ellipsoid may be greater than the radius of the unit ellipsoid, and a portion of the outer boundary of the cavity ellipsoid may pass through the outer boundary of the unit ellipsoid and exist in the outer region of the unit ellipsoid.

In the next step S160, the processor may determine whether the variable k is greater than the random number N generated in the previous step S100. If the variable k is smaller than the random number N ('YES' in step S160), the value of k may be increased by one and the step S120 may be performed. Thereafter, steps S120 to S160 may be repeatedly performed. The iterative process may be repeated until a total of N unit ellipsoids are generated. On the other hand, if the variable k is greater than the random number N ('NO' in step S160), the virtual organoid generation method according to the present specification i) completes the generation of unit ellipsoids and cavity ellipsoids, and ii) proceeds to the generation of organoid chunks. there is.

Referring to FIG. 2 , in step S200, the processor may form a blob that is a union of unit ellipsoids. In step S210, the processor may form a hollow that is a union of common ellipsoids. In step S220, the processor may form a clump, which is the difference between the hollows in the blobs. That is, the processor may generate chunk data by removing the set of common ellipsoids from the set of unit ellipsoids through steps S200 and S220.

5 is a reference diagram for lump data of virtual organoids.

Referring to FIG. 5 , according to the example of N=4, it is possible to confirm a lump in which four joint ellipsoid sets are removed from the four unit ellipsoid sets. Since the virtual organoid according to the present specification is formed in a virtual three-dimensional space, the reference diagram shown in FIG. 4 should be understood as a kind of cross-sectional view for explaining that an empty space is formed inside the chunk data. In this way, the process of expressing a mass with an empty space inside using an ellipsoid is to express the overall appearance of the actual organoid most similarly to the virtual organoid.

On the other hand, although FIG. 5 shows an embodiment in which all unit ellipsoids contact each other to form a lump, the size of the unit ellipsoid is randomly determined in step S120 and the position of the unit ellipsoid is randomly arranged in step S130. Embodiments formed of two or more masses spaced apart from each other are also possible. In addition, although the lump data shown in FIG. 5 shows that a closed space is formed in which the inner space is not connected to the outer space, the inner space of the lump does not necessarily have to be a closed space. Since the size of the cavity ellipsoid is determined in step S140 and the positions of the cavity ellipsoid are randomly arranged in step S150, a lump in which the inside and outside of the lump are connected, that is, a lump in which a partial area is open can be created.

In the next step S230, the processor may convert the clump, that is, chunk data, into voxel data according to a preset resolution. The resolution may be, for example, 256 x 256 x 256, and the resolution may be set in various ways according to the performance of equipment executing the virtual organoid generation method according to the present specification or the purpose of the virtual organoid.

6 is a reference diagram for voxelization.

Referring to FIG. 6 , an example in which a lump in a 3D space is converted into voxels having an arbitrary resolution can be seen. After completing the step of ii) generating an organoid lump in the method for generating a virtual organoid according to the present specification, iii) cell arrangement may be performed.

Referring to FIG. 3 , in step S300, the processor may set a variable k' and input k'=0 as an initial value. In addition, each voxel is expressed as "v _k' ", and the set of all voxels included in the lump is expressed as "V". The variable k' is a variable for executing steps S310 to S340 of randomly arranging cells for all voxels included in V.

In step S310, the processor may set a probability that a cell exists in each voxel (v _k' ). In steps S320 to S340, the processor may determine whether cells are arranged according to the set cell existence probability for each voxel. For example, when the probability of cell presence in a voxel is set to 1/10, the processor may generate a random number M between 0 and 9 for the voxel (v _k' ) according to the probability of cell existence in step S320. In this case, when the random number M=0, it is assumed that a cell exists in the corresponding voxel (v _k' ). If the random number M is not 0 in step S330 ('NO' in step S330), the processor increments the variable k' by one and proceeds to step S310. And steps S310 to S330 may be repeatedly performed. On the other hand, if the random number M is 0 in step S330 ('YES' in step S330), the processor may proceed to step S340. In step S340, the processor may process the cell as being present in the corresponding voxel (v _k' ), and may assign a characteristic value of the arranged cell. The processor may assign at least one of the size, shape, and degree of staining of the cell as a characteristic value of the cell.

7 is a reference diagram for random cell arrangement in voxels.

Referring to FIG. 7 , it can be seen that 16 voxels are displayed, and each voxel is filled with a number. The number represents the random number M generated for each voxel, and cells may exist where the number '0' is displayed.

On the other hand, organoids may consist of only one type of cell, but may consist of two or more types of cells. In order to realize that the virtual organoid is also composed of two or more types of cells, the processor may set a probability so that only one of the two or more cells exists in each voxel in step S310. For example, when generating a virtual organoid composed of two types of cells, the existence probability of the first cell may be set to 1/p and the existence probability of the second cell to 1/q. In this case, each voxel has three cases: the first cell is present (1/p), the second cell is present (1/q), or the cell is not present (1-1/p-1/q). It is possible.

In step S350, the processor may determine whether cell arrangement is determined for all voxels, and may repeat steps S310 to S340. In addition, when cell arrangement is completed for all voxels, creation of virtual organoids may be completed.

The method of generating captured image data using virtual organoids according to the present specification, like the method of generating virtual organoids described above, may be implemented in the form of a computer program that can be executed on a computer. Therefore, in the following description of the method for generating captured image data using virtual organoids according to the present specification, the processing, calculation, output, and various logics of each step are assumed to be executed by a processor known in the art to which the present invention belongs. Let me explain.

Referring to FIG. 8 , in step S400, the processor may set a position of a light source in a virtual 3D space. Characteristic values such as brightness and color of the light source may be variously set by reflecting the actual photographing environment or the characteristics of organoids. As the characteristics of the light source become more diverse, the diversity of finally generated image data may also increase.

Preferably, the processor may set the light source to be located at an upper end in the Z-axis direction from the central region of the virtual organoid. When photographing actual organoids, an environment in which the camera photographs the organoids placed on the culture plate from vertically upward to downward is taken into consideration. Meanwhile, in the present specification, the Z-axis refers to a coordinate axis parallel to a vertical direction excluding the X-axis and Y-axis, which are horizontal and vertical directions among the X-axis, Y-axis, and Z-axis orthogonal to each other.

In the next step S410, the processor may set a focal plane in a virtual 3D space. The focal plane is a concept corresponding to the focal length of the camera. When photographing an actual organoid, there may be cells that are clearly photographed and cells that are photographed in flow depending on the focal length of the camera. For the same virtual organoid, the more diverse the focal plane, the greater the diversity of image data to be finally generated.

Preferably, the processor may set the focal plane to be located within the boundary surface of the virtual organoid. When the focal plane exists outside the boundary of the virtual organoid, an environment in which all cells are blurred when imaging the actual organoid is assumed. Therefore, it is preferable to set the focal plane within the boundary of the virtual organoid, assuming an environment in which some cells in the organoid can be clearly imaged and some cells blurred.

Furthermore, the processor may set the normal of the focal plane to be parallel to the Z-axis of the virtual 3D space. This also takes into account the environment in which the camera shoots the organoids placed on the culture plate from the top to the bottom when actual organoids are photographed. However, the method for generating image data using virtual organoids according to the present specification is not necessarily limited to vertical shooting, and the normal line of the focal plane may be tilted with respect to the Z axis.

In the next step S420, the variable k'' may be set, and "k''=0" may be input as an initial value. The variable k″ is a variable for performing calculations on all cells (S _k″ ) in the virtual organoid.

In step S430, the processor may calculate the brightness and sharpness of each cell in the virtual organoid in consideration of the position of the light source and the position of the focal plane.

9 is a reference diagram for calculating brightness and sharpness of cells.

Referring to FIG. 9 , three cells (S ₁ , S ₂ , and S ₃ ) disposed in the virtual space, a light source, and a focal plane can be confirmed. And the focal plane is aligned with the cell S ₂ . The processor may calculate the brightness of each cell in inverse proportion to the square of the distance between the light source and each cell (1/D _L ² ). The processor may calculate the sharpness of each cell in inverse proportion to the square of the distance between the focal plane and each cell (1/D _F ² ). Furthermore, the processor may calculate the brightness and sharpness of the cells by further considering the degree of staining of the cells. If the above content is expressed as a formula, it is as follows.

In step S440, the processor may determine that brightness and sharpness calculation is completed for all cells (S _k″ ). If calculation is not completed for all cells ('NO' in S440), steps S430 and S440 may be repeatedly executed. On the other hand, when the calculation is completed for all cells ('YES' in S440), it is possible to proceed to step S450.

In step S450, the processor may generate captured image data of the virtual organoid reflecting the calculated brightness and sharpness of the cells.

10 is an example of a photographed image of a virtual organoid.

Referring to FIG. 10 , it is possible to see an image in which the brightness and sharpness of the cells S ₁ , S ₂ , and S ₃ shown in FIG. 9 are expressed differently depending on the distance between the light source and the focal plane.

11 is another example of a captured image of a virtual organoid.

Referring to FIG. 11 , when an empty space is formed therein, it is possible to check an image generated by various cells disposed in the boundary area according to brightness and sharpness. That is, the method for generating image data using a virtual organoid according to the present specification can generate image data that can have the same effect as capturing an actual organoid.

Although the embodiments of the present specification have been described with reference to the accompanying drawings, those skilled in the art to which the present specification pertains can be implemented in other specific forms without changing the technical spirit or essential features of the present invention. you will be able to understand Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

The above-described program is C / C ++, C #, JAVA, Python, which can be read by a processor (CPU) of the computer through a device interface of the computer so that the computer reads the program and executes the methods implemented in the program. , and may include codes coded in computer languages such as machine language. These codes may include functional codes related to functions defining necessary functions for executing the methods, and include control codes related to execution procedures necessary for the processor of the computer to execute the functions according to a predetermined procedure. can do. In addition, these codes may further include memory reference related codes for which location (address address) of the computer's internal or external memory should be referenced for additional information or media required for the computer's processor to execute the functions. there is. In addition, when the processor of the computer needs to communicate with any other remote computer or server in order to execute the functions, the code uses the computer's communication module to determine how to communicate with any other remote computer or server. It may further include communication-related codes for whether to communicate, what kind of information or media to transmit/receive during communication, and the like.

The storage medium is not a medium that stores data for a short moment, such as a register, cache, or memory, but a medium that stores data semi-permanently and is readable by a device. Specifically, examples of the storage medium include ROM, RAM, CD-ROM, magnetic tape, floppy disk, optical data storage device, etc., but are not limited thereto. That is, the program may be stored in various recording media on various servers accessible by the computer or various recording media on the user's computer. In addition, the medium may be distributed to computer systems connected through a network, and computer readable codes may be stored in a distributed manner.

Claims

As a method of generating organoids in a virtual three-dimensional space, a processor

(a) generating a random number and generating as many unit ellipsoids according to the generated random number;

(b) setting and arranging the center point of each unit ellipsoid generated in step (a) at arbitrary coordinates in a three-dimensional space;

(c) generating as many cavity ellipsoids as the number of unit ellipsoids whose center points exist inside each unit ellipsoid;

(d) generating lump data by removing the set of common ellipsoids from the set of unit ellipsoids;

(e) converting the chunk data into voxel data according to a preset resolution; and

(f) randomly arranging cells with respect to the voxel;
The method of claim 1,

The step (a) is a step of generating a diameter length and a rotation angle with respect to three axes orthogonal to each other with the center point of each unit ellipsoid as the origin using random numbers.
The method of claim 1,

The step (b) is a step of arranging the center point so that the boundary of each unit ellipsoid exists in a virtual three-dimensional space.
The method of claim 1,

The step (c) is a step of generating a diameter length and a rotation angle with respect to three axes orthogonal to each other with the center point of each cavity ellipsoid as the origin using random numbers.
The method of claim 1,

The step (f) is

(f-1) setting a probability that a cell exists in each voxel; and

(f-2) determining whether to place cells according to the set cell existence probability for each voxel;
The method of claim 5,

When there are two or more different cells

The step (f-1) is a step of setting a probability so that only one cell among two or more cells exists in each voxel.
The method of claim 1,

The virtual organoid generation method further comprising: (g) assigning characteristic values to the arranged cells.
The method of claim 7,

Wherein step (g) is a step of assigning at least one characteristic value among cell size, shape, and degree of staining to the virtual organoid.
A computer program written in a computer to perform each step of the virtual organoid generation method according to any one of claims 1 to 8 and recorded on a computer-readable recording medium.
A device for generating organoids in a virtual three-dimensional space,

A random number is generated, as many unit ellipsoids as the number according to the generated random number are generated, the center point of each generated unit ellipsoid is set and arranged at an arbitrary coordinate in the 3D space, and the center point is located inside each unit ellipsoid. As many ellipsoids as the number of unit ellipsoids are generated, a set of joint ellipsoids is removed from a set of unit ellipsoids to generate chunk data, the chunk data is converted into voxel data according to a preset resolution, and the voxels are randomly selected. A virtual organoid generating device comprising a; processor for disposing the cells into;